Renal transplantation is the definitive therapy for chronic renal failure and has improved the quality of and prolonged the life of thousands since its inception over three decades ago. Despite significant advances in understanding of tissue typing and immunosuppression and the availability of better immunosuppressive agents, acute rejection remains a serious clinical problem. In the absence of successful therapies, rejection will lead to graft failure in some patients, requiring reinstitution of dialysis and the search for another donor kidney. With the use of cyclosporine in conjunction with other immunosuppressive agents, the one-year graft survival rate for cadaver allografts is in the range of 80%, but graft half-life remains less than optimal in the range of 7.2 years. Kirkman et al., Transplantation, 1991:51:107-113. Other types of solid organ transplantation, e.g., heart, liver and lung, also save the lives of thousands of patients each year, but here also acute rejection remains a serious clinical problem only partially controlled by current immunosuppressive drugs.
Current immunosuppressive therapy for acute rejection associated with renal or other solid organ transplantation consists of multiple drugs that interfere with the function of the immune system at various levels. In addition to the complications of over-immunosuppression that may result from the use of multiple drugs, each has its own unique toxicity profile, which may limit its usefulness.
T lymphocytes are known to play a key role in allograft rejection. Activated T lymphocytes have been identified as IL-2 receptor bearing cells. Several murine anti-IL-2 receptor antibodies have been administered in clinical trials for the prophylaxis and treatment of allograft rejection. Carpenter, CB et al., Am J. Kid Dis. 1989:14:54-57; Kirkman, RL et al., Transplantation, 1991:51:107-113 (anti-Tac); Soulillou, PJ et al., Lancet, Jun. 13, 1987:1339-1342; Soulillou, JP et al., N Eng J Med, 1990:322:1175-1182 (33B3.1); Herve P et al., Blood, 1990:75:1017-1023 (B-B10); Nashan et al., Transplantation, 1996:61:546-554.
Murine anti-Tac is a monoclonal antibody that binds to the p55 subunit of the IL-2 receptor of human T and B lymphocytes, blocking the formation of the high-affinity IL-2 receptor and subsequent activation by IL-2. The ability of murine anti-Tac ("MAT") to decrease the number of acute rejection episodes and to delay the first rejection episode following cadaveric renal allograft has been analyzed. Kirkman, RL et al., Transplantation, 1991:51:107-113. For 80 patients randomized to receive either standard immunosuppressive therapy (cyclosporine 8 mg/kg/day, prednisone, and azathioprine) or a reduced dose of cyclosporine (4 mg/kg/day), prednisone, azathioprine, and MAT for 10 days post transplantation, the number of patients experiencing an acute rejection episode in the first 10 days post transplant was significantly less in the MAT group as compared with the standard group (5/40 vs. 21/40, p&lt;0.001). In addition, the time to the first rejection episode was greater in the MAT group (12.5 days vs. 7.6 days, p&lt;0.05). However, eventually, the number of rejection episodes between the two groups was not statistically different: 14/40 in the MAT group and 24/40 in the standard group. Further, antibodies to MAT were detected in 7 of 10 patients tested.
Development of an immunogenic response is typical when a mouse antibody is injected into human patients. That is, the injected mouse antibodies are recognized by the immune system as foreign proteins and provoke a human anti-mouse antibody (HAMA) response, which rapidly neutralizes the mouse antibodies and renders them ineffective for further therapy. It has been proposed that the HAMA problem can be reduced or eliminated by use of genetic engineering to transform mouse monoclonal antibodies into more human-like antibodies, utilizing the understanding of antibody structure that scientists have obtained.
Zenapax.RTM. (dacliximab) is a humanized anti-Tac ("HAT") antibody, a humanized form of murine anti-Tac described in U.S. Pat. Nos. 5,530,101 and 5,585,089 and Queen et al. 1989:86:1029-10033, all of which are incorporated herein by reference. HAT comprises heavy and light chain variable domains having amino acid sequences designated SEQ. ID. No. 1 and SEQ. ID. No. 2 respectively. Studies of HAT in primate transplant models have reported HAT to be less immunogenic than MAT and to have a longer half-life. Hakimi et al., J. Immun. 1991:147:1352-1359.
The safety and pharmacokinetics of a single IV administration of HAT has been evaluated in a Phase I study. Six patients having Tac-bearing tumors received a single dose of Zenapax.RTM. and were followed for 56 days. Four patients received 0.5 mg/kg, and two received 1.0 mg/kg. The only HAT-related adverse events reported were hives, flank pain, and lower extremity pain and edema in one patient who received 0.5 mg/kg of Zenapax.RTM.. No tumor responses were observed. One patient who received 0.5 mg/kg of HAT developed an anti-idiotypic antibody to HAT.RTM..
A second phase I study in patients with steroid-resistant acute graft-versus-host disease ("GVHD") was conducted at two centers. Anasetti, C. et al., Blood, 1994:84:1320-1327. One center was Fred Hutchinson Cancer Research Center in Seattle, Wash. A second center was Vancouver General Hospital in Vancouver, Canada. In the published study, between the two centers, four patients received a single dose of HAT of 0.5 mg/kg, four patients received a single dose of Zenapax.RTM. of 1.0 mg/kg, and twelve patients received a single dose of Zenapax.RTM. of 1.5 mg/kg, with a maximum dose of 100 mg. No serious adverse events related to HAT were noted. The only two adverse events felt to be possibly related to HAT were diaphoresis in one patient and chills in another, both at the 0.5 mg/kg level. The protocol allowed for re-treatment at the same dose level, and eight patients received a second dose. No acute adverse events were reported with re-administration of Zenapax.RTM.. Patients were evaluated for response on day 29, and 4 had a complete response and 4 had a partial response. Responses were seen at all dose levels, and no dose response relationship was seen. Fluorescent activated cell sorter analysis of peripheral blood lymphocytes showed that HAT was bound to the Tac (p55) portion of the IL-2 receptor for up to 28 days following a single dose of Zenapax.RTM.. All but one patient who survived &gt;100 days developed chronic GVHD. None of the patients developed anti-HAT antibodies.
Additional patients with steroid-resistant GVHD were treated with a single dose of Zenapax.RTM. in 3 centers in Italy. Pinto R. M., 21st Meeting of the EMBT, Davos, Switzerland, March 1995. Patients were followed for safety, efficacy and pharmacodynamics. No serious adverse events related to HAT were reported, and 3 patients achieved a response.
A phase II/III, blinded, placebo-controlled, multidose trial for the prevention of acute GVHD in bone marrow transplantation was conducted at 12 centers. Anasetti, C., Blood 1995:86, Supplement 1:621a. In addition to a standard immunosuppressive regimen of cyclosporine and methotrexate to prevent GVHD, patients were treated with placebo, Zenapax.RTM. 0.3 mg/kg, or Zenapax.RTM. 1.2 mg/kg weekly for five doses beginning the day before bone marrow transplantation. However, no significant difference in the incidence of acute GVHD in the placebo and Zenapax-treated groups was observed, that is, Zenapax.RTM. was not effective in the prevention of graft-versus-host disease in this study.
A phase I, randomized, open label, multidose study in patients receiving first renal transplants was conducted at two centers. The purpose of the study was to evaluate the safety, pharmacokinetics-dynamics and immunosuppressive effect of HAT. In one center, 12 patients were evaluated. Vincenti, F. et al., Proceedings of the 14th Annual Meeting of the American Society of Transplant Physicians, Chicago, Ill., May 14-17, 1995, p. 90 (abstract 68); Vincenti et al., Transplantation 1997:63:33-38. Ten patients received living related transplants (3 HLA identical and 7 one and zero haplotype match) and two patients received cadaveric transplants. Of the 12 patients, 4 received 0.5 mg/kg/week of Zenapax.RTM.; 3 received 0.5 mg/kg/every other week of Zenapax.RTM.; 2 received 1 mg/kg/week of Zenapax.RTM.; and 3 received 1 mg/kg/every other week of Zenapax.RTM.. All three patients receiving 1 mg/kg/every other week of Zenapax.RTM. received living related transplants. Zenapax.RTM. was administered intravenously over 30 minutes to all patients in combination with standard three-drug immunosuppressive therapy (cyclosporine, azathioprine, and prednisone), for a total of five doses. The first dose of Zenapax.RTM. was given within 12 hours prior to transplantation and the 4 additional doses were given in the weeks following transplantation. No serious adverse events possibly or probably related to HAT have been reported. One rejection episode was experienced on day 7 by a patient who received a cadaveric transplant and had been randomized to receive Zenapax.RTM. at a dose of 0.5 mg/kg/every other week. One patient developed low-titer anti-HAT antibodies. Pharmacokinetics-dynamics results indicated that Zenapax.RTM. given at 1 mg/kg/every other week results in good saturation of Tac receptors. Based on this study HAT appears to be safe and well tolerated by patients. However, no conclusions on the efficacy of Zenapax for prevention of kidney transplant rejection could be drawn from this small, phase I study which had no placebo control group.